FBXW7 mitigates hepatic fibrosis by degrading NOTCH1 to transcriptionally silence SEMA3G in liver sinusoidal endothelial cells

Overactivation of Notch signaling in liver sinusoidal endothelial cells (LSECs) is an established driver of hepatic fibrosis, yet its precise upstream regulators and downstream effectors remain poorly defined, limiting therapeutic translation. Here, we demonstrate that FBXW7, the primary E3 ubiquitin ligase responsible for NOTCH1 degradation, serves as a critical suppressor of liver fibrosis. Using endothelial-specific Fbxw7 knockout mice subjected to three distinct fibrosis models, we show that FBXW7 loss exacerbates liver fibrosis, promotes LSEC capillarization, and enhances hepatic stellate cell activation. Transcriptomic analysis identified Sema3g as the top upregulated gene in FBXW7‑deficient LSECs, and conditioned medium from these cells stimulated HSC activation through SEMA3G‑dependent paracrine signaling. Moreover, nanoparticle-mediated delivery of Sema3g-targeting siRNA specifically to LSECs substantially ameliorated injury-induced liver fibrosis in Fbxw7 knockout mice. Mechanistically, FBXW7 loss stabilizes NOTCH1, leading to enhanced Sema3g transcription. Consistent with these findings, human cirrhotic samples and murine fibrotic livers exhibit reduced FBXW7 expression alongside elevated active NOTCH1 and SEMA3G in LSECs. Collectively, our results demonstrate that FBXW7 mitigates liver fibrosis by degrading NOTCH1 to transcriptionally silence SEMA3G, and suggest that targeting the FBXW7/NOTCH1/SEMA3G axis represents a promising therapeutic strategy for fibrotic liver disease. The authors reported a randomized trial showing that transcutaneous auricular vagus nerve stimulation reduces postoperative liver injury in patients undergoing partial hepatectomy.